Severe immediate hypersensitivity to gadolinium contrast agent after targeted treatment in a patient with alveolar soft part sarcoma: A case report and review of literature

Rationale: Gadolinium-based contrast agents (GBCAs), benefiting from good tolerance and safety, become the priority contrast agents in magnetic resonance imaging. Serious hypersensitivity reactions caused by GBCAs are rare, but occur occasionally. The “immune surveillance” theory proposes that lowered immune function exists in patients with malignance, which decrease the occurrence of atopy. Natural immunosurveillance that enhanced by effective treatment of malignance may increase the risk of hypersensitivity. Patient concerns: A 29-year-old female patient suffering from intensive pain with left leg mass was admitted in our hospital. Diagnoses: The patient was diagnosed with alveolar soft part sarcoma by histopathology and revealed destruction of the left fibula and lung metastasis by computed tomography scan, and treated with anlotinib hydrochloride, a multi-targeted tyrosine kinase inhibitor. After 4 cycles of effective targeted therapy, the patient developed severe immediate hypersensitivity due to gadopentetate dimeglumine-enhanced magnetic resonance imaging. Interventions and outcomes: The vital signs of the patient returned to normal after rescue. Since then, the patient has not used gadolinium contrast agent again, and currently the condition is stable and still alive. Lessons: Severe immediate hypersensitivity might be occurred by gadolinium contrast agent in patients with malignance after effective treatment. We explored the potential mechanism of GBCA-inducing hypersensitivity in detail, by especially focusing on the changes of immune environment. Furthermore, we propose new ideas for the safe use of GBCAs in patients with malignancies.


Introduction
Contrast-enhanced magnetic resonance imaging (MRI) provides the necessary imaging evidence for the clinical diagnosis and curative effect evaluation of malignant tumors.Since the 1980s, gadolinium-based contrast agents (GBCAs) have been the main pillar in clinical diagnosis as they enhanced the resolution of MRI, and improved the detection rates of micro lesions, which show good tolerance and safety. [1]Adverse reactions related to GBCAs have been gradually reported [2][3][4] with the increase of their application.Though most of the GBCAs' adverse effects were mild, more serious or even lethal events should attract more attention to ensure their safety usage.Patients with malignancies are more frequently exposed

This research was supported by the grants from the Scientific Research Project of Health Commission of Shanxi Province (2020063) and the Natural Science Research Project Department of Science and Technology of Shanxi Province (202203021221280).
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
to GBCAs for periodic assessment of therapeutic regimen.Immunodeficiency is common in patients with malignancies, which is associated with generally low incidence rates of hypersensitivity. [5]However, in this case, the serious immediate hypersensitivity caused by gadopentetate dimeglumine (Gd-DTPA), which is the first linear ionic GBCA for enhanced MRI, had not been avoided.
The purpose of our work was to report an extremely rare case of hypersensitivity induced by GBCAs.In addition, we not only analyzed the possible mechanisms of inducing severe immediate hypersensitivity and the corresponding countermeasures, but also proposed a new viewpoint for the clinical management of GBCAs in patients with malignant tumors.

Case presentation
A 29-year-old female patient (height, 173 cm; weight, 63 kg) suffering intensive pain with left leg mass for >1 month was admitted in our hospital.She was diagnosed with alveolar soft part sarcoma by histopathology (Fig. 1), and computed tomography scan showed destruction of the left fibula and lung metastasis.She denied any history of food and drug allergies or asthma.She was treated with anlotinib hydrochloride, a multi-targeted tyrosine kinase inhibitor on 20, 2020.The patient underwent contrast-enhanced MRI of the left tibiofibular bone using 20 mL gadodiamide (Gd-DTPA-BMA) on July 14 and September 8, 2020.To evaluate the therapeutic effect of 4 cycles of anlotinib hydrochloride, 15 mL Gd-DTPA (Magnevist, Bayer, Batch number KT05TTJ) were used for the left leg MRI enhanced scan on November 12, 2020.Approximately 2 minutes after the Gd-DTPA injection, the patient raised her hand to indicate discomfort, presented with nausea and vomiting, and a pale face.The MRI medical staff stopped the machine urgently and transferred the patient to a stretcher for electrocardiogram, blood oxygen saturation, and blood pressure monitoring.At this time, the patient's blood pressure and heart rate could not be measured and she could not respond to inquiries.The medical staff immediately established the venous pathway and administered oxygen therapy.In addition, epinephrine (0.5 mg, 1 g/1000 mL) was administrated intramuscularly, methylprednisolone (40 mg) was injected intravenously, and diphenhydramine (20 mg) was injected intramuscularly.Ten minutes later, she gradually developed spontaneous breathing and consciousness.Physical examination revealed a blood pressure of 48/29 mm Hg and a heart rate of 135 bpm.The patient was administered a 200 mg intravenous drip of dopamine and a 500 mL hydroxyethyl starch injection for volume expansion.After 10 minutes, the patient's blood pressure was 80/50 mm Hg.The patient was conscious and was transferred to intensive care unit for further treatment.After 12 hours of acid suppression and maintenance of water and electrolyte balance in the intensive care unit, the patient's vital signs were stable the next morning, and she was transferred to the general ward to continue primary treatment.After 3 days of primary treatment, the patient was discharged.

Discussion
The case was a severe immediate hypersensitivity reaction that occurred in a patient with a malignant tumor when she underwent enhanced MRI to evaluate the efficacy of 4 cycles of anlotinib hydrochloride.The patient was diagnosed with anaphylactoid shock induced by Gd-DTPA given the time relationship between symptom onset and injection, and rescued in time.Of note, the patient did not have any adverse reactions after using Gd-DTPA-BMA twice before, but there was a serious immediate hypersensitivity reaction with Gd-DTPA during the third MRI.We explored the potential mechanisms from patients and drugs to disease.
[4] In particular, the incidence of instant hypersensitivity in patients increased with an increase in exposure time to MR contrast agents.In this case, the patient had no history of food or drug allergies and had been exposed to GBCA twice before, without any problems.Therefore, age, sex, and previous repeated usage of GBCA played an important role in the severe immediate hypersensitivity induced by GBCAs.
Second, the chemical structure of a drug is related to its hypersensitivity reactions.GBCAs are divided into ionic and nonionic types, such as Gd-DTPA and Gd-DTPA-BMA, according to their net charge.Raisch et al suggested that Gd-DTPA caused more anaphylactic shock than Gd-DTPA-BMA. [6]d-DTPA is characterized by the presence of ionic bonds in the chemical structure of molecules and the existence of free ion residues in solution, which increases the toxicity of drug ecological agents and reduces their biological tolerance. [7]In contrast, due to the existence of ionic bonds, Gd-DTPA has a higher  osmotic pressure than Gd-DTPA-BMA.Hyperosmolalityrelated direct membrane effects, complement activation, and immunoglobulin E (IgE)-mediated effects can lead to hypersensitivity.Furthermore, these molecules are classified based on their molecular structure (being linear or macrocyclic) as well as their net charge.Macrocyclic chelation ligands are more stable, which may be relevant for toxicity.Some researchers believe that the direct effect on basophils or mast cell membranes is related to the chemical structure or osmotic pressure of the contrast medium. [8]Structural features and osmolality of various GBCAs used in clinic were displayed in Table 1.regard to hypersensitivity induced by GBCAs, Galera et al [9] reported that hyperosmolar GBCAs might be IgE mediated rather than nonspecific histamine release, and the more serious the reaction was, the more likely it was to involve the IgE-mediated mechanism.Finally, we speculate that a hypersensitivity reaction was related to the natural immunosurveillance that enhanced by effective treatment of malignance.The "immune surveillance" theory proposes that enhanced immune responsiveness may be provoked atopy, which defined by exaggerated IgE responses.[12] The IgE levels of patients with malignant tumors are often much lower than those of the general population, less susceptible aroused hypersensitivity. [5]upporting evidence shows that solid tumors are most common in IgE-deficient patients. [13][16] High IgE levels may reflect the natural activation of immune monitoring mechanisms.Early studies showed an increased risk of IgE-mediated type I hypersensitivity in some patients with head and neck cancer after targeted drug therapy. [15]The patient was diagnosed with alveolar soft part sarcoma and received 4 targeted therapy sessions with arotinib hydrochloride.Alveolar soft part sarcoma that shows insensitivity to radiotherapy and chemotherapy, is a rare soft tissue sarcoma with high risk of lung and brain metastases.Targeted drugs are more effective for it.Arotinib hydrochloride is a multi-target tyrosine kinase inhibitor that inhibits tumor proliferation and angiogenesis.When the malignant tumor was effectively controlled with targeted therapy (Fig. 2), immune monitoring might be activated, and IgE level was elevated, which increased the risk of severe hypersensitivity.Unfortunately, the IgE was not collected during therapy in this report because it was not awarded a priori that natural immunosurveillance would be enhanced by effective treatment of malignance.Henceforth, the patient still received targeted therapy, but no gadolinium contrast agent was used again.
According to the literatures of severe immediate hypersensitivity due to gadolinium contrast agent in patients with malignances, only 9 reports were found [17][18][19][20][21][22][23][24][25] summarized in Table 2.The treatment of malignances was not mentioned in literatures.Patients who experienced severe hypersensitivity with Gd-DTPA also had a higher incidence of prior allergic events, with 3 of 4 patients having a history of allergy to something.Severe immediate hypersensitivity was caused by macrocyclic GBCAs in the remaining 5 reports.These cases suggest that we should pay more attention to patients with malignant tumors, even if they did not have any discomfort in previous usage of GBCAs.
However, there is no clear prophylactic management for serious immediate hypersensitivity reactions caused by gadolinium contrast agents.There are different preventive measures for patients with a history of allergies.First, the American Society of Radiology recommends the use of antihistamines and corticosteroids as premedications.At the same time, it also pointed out that premedication might cause breakthrough reactions, which also caused allergic reactions. [1]Second, similar to iodine contrast agents, the European Academy of Allergy Asthma and Clinical Immunology Guidelines propose that patients with an allergic history should undergo skin tests before using contrast agents.[28] Third, some researchers have suggested general anesthesia to prevent hypersensitivity in patients with an allergic history.General anesthesia inhibits consciousness-dependent reactions, such as anxiety and autism phobia, but does not suppress the release of basophils and mast cells induced by iodide or GBCAs, and the subsequent immediate hypersensitivity. [29]evertheless, these measures have their own benefits and drawbacks.We try to find a method for the safe use of GBCAs in patients with malignant tumors, which is more frequently exposed to GBCAs and has its own particularity.The immune function of cancer patients is low.After treatment, it may increase the concentration of IgE and the risk of its mediated hypersensitivity.Therefore, we suggest that IgE should be detected regularly during cancer treatment.Before using GBCAs, the risk of allergic reactions can be judged by comparing the IgE levels in the last 2 times, and medical staff should also take measures against rare reactions.Moreover, a comparison of IgE expression differences can also be used to infer the safe use of other drugs that induce hypersensitivity to IgE.

Conclusions
In conclusion, although GBCAs show good safety and tolerance, more attention should be paid to the occurrence of hypersensitivity in patients with malignancy.We analyzed the reasons for hypersensitivity, including age, sex, previous repeated use, ionic and high osmotic GBCA, and changes in IgE levels.It has been proposed that IgE is an important indicator for evaluating the hypersensitivity reaction of patients with malignant tumors during treatment, which enriches the clinical management of patients.

Table 1
Structural features and osmolality of gadolinium-based contrast agents.